Pharmaceutical Mega-Deals Could Delay RNA Therapeutics Partnerships

Pharmaceutical mega-deals are en vogue again.  Though not official, rumor is that Pfizer intends to acquire AstraZeneca for $100B, and deal engine Valeant has gone hostile on Botox maker Allergan with a ~$45B bid.  As if that weren’t enough for what was supposed to be a quiet Easter weekend, double-digit billion figures are being moved across the table in an asset swap between Novartis and GSK.   

The motivations for all these deals are essentially the same: squeezing out short-term profits by slashing R&D.  Valeant is an interesting example as it never pretended to be in the R&D game in the first place.  Instead, it exists on the notion that R&D is inefficient and risky and financial engineering through M&A instead of drug development is the only way to Big Pharma bliss.  Considering its spectacular rise to a ~$50B market cap company and a relentless increase in its share price, it has the goods to show for it. 

Pfizer, on the other hand, like all Big Pharmas likes to tout its R&D prowess webcast after webcast, R&D day after R&D day, but in fact is the worst offender when it comes to squeezing profits from slashing R&D.  In just 5 years following its acquisition of Wyeth, the R&D budget of the combined companies has been cut in half.  AstraZeneca is partly a juicy target because it was forced to be more risk-taking in its R&D as it gained the reputation to be the Big Pharma with the least innovative and effective R&D. 

As a consequence of this, AstraZeneca has become one of the most active Big Pharma in RNA Therapeutics with deals in antisense (ISIS), microRNAs (Regulus), RNA modulation (PTC Therapeutics), and most famously the 2013 $240M upfront mRNA Therapeutics deal with Moderna. 

Unfortunately/fortunately, depending on whether you think Big Pharma involvement in RNA Therapeutics is a good thing or not, the other two deal protagonists from this weekend, Novartis and GSK are also amongst the Big 4 Pharmas in RNA Therapeutics (Sanofi/Genzyme being the 4^th).

In addition to cost savings by cutting R&D outright, RNA Therapeutics deals could also be affected by Big Pharmas becoming pre-occupied with re-organizing.  This is based on experience as the narrative is that when Pfizer acquired Wyeth in 2009, Wyeth had by far the superior RNAi development effort, but that this fell victim to the acquisition.  Similarly, when Roche acquired Genentech the same year, RNAi Therapeutics quickly fell down the priority list.

What deals may be canceled or at least delayed as a result of these developments? 

mRNA delivery is the first one that comes to mind as I believed AstraZeneca to be under pressure to do something in this area after having spent probably $300M on mRNA Therapeutics by now.  

We have already heard about Novartis which had been another top pick for a delivery deal to go with its target picks from Alnylam.

Fortunately, RNA(i) Therapeutics is in a different position from what it was in 2009.  Cashed up and with robust, clinically validated technologies, a number of companies do not depend on dilutive Big Pharma deals any more- at least for now.  Let the deals therefore happen.  They will only accelerate the demise of the old pharmaceutical model to be replaced by innovative biotech companies.  

Journal Club: Study Shows TLR3 Induction by siRNAs with Anti-angiogenic Effects, Questioning Ongoing RNAi Clinical Trials for Wet AMD

RNAi is a relatively young therapeutic platform and we are rapidly learning about the gene-specific and non-specific effects of RNAi triggers in vivo. Ultimately, the value of RNAi Therapeutics lies in the gene-specific knockdown of therapeutic target genes, but it is clear that non-specific class effects may confound the analysis of pre-clinical and clinical results. This is especially true for a number of the early RNAi Therapeutics candidates that entered the clinic at a time when less was known about issues such as off-targeting, cytokine induction via TLR-7, and now also TLR3.

The study by Kleinman et al. from the University of Kentucky that appeared yesterday in the high-profile journal Nature (Nature doi 1038/Nature 06765), investigated siRNA therapy for wet age-related macular degeneration (AMD). Of note, there are at least 3 RNAi clinical trials ongoing for AMD: a phase III candidate by Opko Health, bevasiranib, involving intravitreal injection of an unmodified siRNA against VEGF; a phase II candidate by Allergan/Merck(Sirna Therapeutics) involving a chemically modified siRNA against VEGF-R1, also intravitreally injected; and last but not least a phase I, likely intravitreally injected “AtuRNAi” compound targeting a novel, non-VEGF pathway gene by Pfizer/Quark Biotech. Kleinman and colleagues showed that pretty much all of the siRNAs they injected, 2’O-methyl modified (Allergan drug) or not (Opko), suppressed laser-induced choroidal neovascularisation (CNV) in mice, a commonly used model for wet AMD, independent of whether their sequence was directed against an angiogenesis gene or not. Furthermore, such siRNAs were not taken up by the cells in the back of the eye, consistent with a lack of target gene knockdown. Through a series of elegant experiments, they showed that this non-specific antiangiogenic effect was mediated by binding of the dsRNA to the TLR3 receptor on the cell-surface of endothelial cells and the subsequent induction of IL-12 and interferon gamma, both of which alone could account for the observed CNV suppression.

At the moment, I cannot explain the discrepancy between these data and studies by the Opko (formerly Acuity) and Sirna Therapeutics groups that showed sequence-specific down-regulation of target-genes and cellular uptake of siRNAs using the same methods employed by the Kentucky group. Be that as it may, since TLR3 receptors are known to bind dsRNA and upregulate the IL-12 cytokine and interferon-gamma and it always amazed me how unformulated siRNAs may so efficiently be taken up in the eye, the conclusions of the studies appear credible. This receptor is different from the cytokine induction potential via TLR-7 which can be abrogated by chemical modifications, particularly 2’O-methyl.

Well, that’s the bad news. But there is also reason to be optimistic. Importantly, the authors showed that by conjugating a VEGF siRNA to cholesterol, the siRNAs were taken up into the cells and were able to knockdown its target gene and reduce CNV, even in mice lacking TLR3. All of this was achieved at the remarkably low amount of only 1ug administered siRNA per eye. This shows that RNAi could still be used very efficiently in a gene-specific manner to address AMD. Interestingly, a cholesterol-conjugated siRNA for VEGF-R1, the target for the Allergan/Merck drug, failed to ameliorate CNV, casting a doubt on the viability of this gene target that’s been relatively little characterized in the context of wet AMD. However, one should add that only one siRNA was tested for this and at the low 1ug dosage.

Cholesterol conjugation for siRNA delivery was first pioneered by Alnylam, and from recent presentations it appears that this is becoming an increasingly important technology, particularly with the elucidation of its uptake pathway in a recent Nature Biotech paper.

The authors further found that TLR induction was dependent on the length of the siRNA. DsRNAs of 21bp or longer induced this response, smaller ones did not. Also, it is very likely that this response to 21bp dsRNAs and longer could be abrogated by chemical modifications. Moreover, it would be interesting to speculate that since TLR3 is a dsRNA-specific binding protein on the cell surface, one may even harness this binding property for siRNA delivery if binding could be separated from TLR3 activation and demonstrated in the article for small dsRNAs.

Finally, as we learn more about these potential non-specific class effects of RNAi triggers (in this case synthetic dsRNAs, not DNA-directed RNAi), strategies can be designed to either avoid them by the judicious design of siRNAs (chemical modifications, length and structure of RNAi trigger) or even harnessed for a synergistic therapeutic effect. Although the number of supplemental figures of this paper (!) would indicate that there had been considerable resistance to the publication of this study, studies like this are extremely valuable in informing future RNAi development programs. This information can also be used to better monitor the safety of RNAi drug candidates already in clinical trials that may very well depend on such non-specific effects for therapeutic efficacy. Even for these drugs, not all hope is lost as firstly it remains to be seen whether and how these mouse studies would translate into the human setting. It is also true that many approved drugs work, but not through their anticipated mechanism of action, and some of the future RNAi drugs may be no exception to this.

The Risk of Rushing RNAi Therapeutics into the Clinic

RNAi has always caught on very fast. It took only nine years for the Nobel Committee to recognize the importance of RNAi in medical biology and award The Prize for its discovery, and only 6 years following the discovery that siRNAs induce RNAi in mammalian cells by Tuschl to become an indispensable tool in the basic and applied studies of human gene function. Equally astounding is the fact that there are now close to 10 RNAi-based therapeutics that have entered the clinic since.

I have extensively described here before why I think RNAi has the potential to be the next great drug development engine, including the prospect of faster development timelines due to straight-forward mechanism of action and platform reproducibility. However, in the wake of Alnylam’s Q3 conference call announcing an insignificant delay in their RSV program, but a more open-ended delay in their liver programs, what I would like to do today is to point out the dangers of rushing RNAi Therapeutics into the clinic mainly borne out of the tension that exists between applying the best and safest science and satisfying investor demand for gushing clinical pipelines.

From the clinical perspective the ultimate danger is obvious: putting trial participants at risk, and disappointing patients’ expectations for a cure of their disease. From the perspective of running an early-stage biotech business that needs to raise money fairly regularly, the issues easily become more complicated. Although I admire the honesty and scientific intent that underlie statements like that by Nastech that one should not expect RNAi Therapeutics from your company until another 15 years, it certainly won’t capture the imagination of Wall Street. The easy way would be therefore to set your bar a little bit lower and signal to your potential investors that you deserve more money since you’ve been able to put so many drugs into the clinic in such a short period of time. A sophisticated biotech investor would know that these companies can be a good investment, although you do not necessarily want to stick it out until the Day of Reckoning comes.

The danger to the field of RNAi Therapeutics is therefore that as some of these rushed candidates come to a stage where they have to prove their safety and efficacy in large-scale clinical trials, a good number of them will fail, essentially because some of the Best Practices were not followed, including addressing cytokine induction issues, off-targeting profiles, RNAi delivery, and pre-clinical safety and efficacy studies that ideally include non-human primates.

Acuity Pharmaceuticals (now part of Opko Health) dazzled everybody when they came out of nowhere and can now claim to have been the first to put an RNAi candidate (for wet AMD) into the clinic. Unless they have changed the composition of their drug since study initiation, Cand5 appears to be an unmodified siRNA injected straight into the eye. This alone makes me wonder whether an optimized compound has been put into the clinic, and I have more confidence in a program run by Allergan and Sirna Therapeutics (Merck) targeting the same pathway for wet AMD, but with a modified siRNA formulation intended for slow release.

SiRNAs that induce cytokine responses may also have a number of additional biological properties, some of them even potentially beneficial for the disease at hand. Gunther Hartmann from Bonn, a scientist with a cytokine angle on oligonucleotide therapeutics, has even proposed at the recent OTS meeting to purposefully combine the immunostimulatory potential of RNAs (isRNA) with siRNA design. Cancer and infectious disease may be good areas to test this concept as isRNAs are thought to help the immune system in fighting related these diseases.

There has been similar discussion whether there would indeed be any harm if an RNAi therapeutic targeting the Hepatitis C Virus (HCV) had some concomitant interferon response. Isn’t interferon (and RNAi) nature’s first answer to viral infections and the mainstay of current HCV treatment regimens anyway? Similar arguments may also apply to RSV.

The fact that Alnylam is now focusing RSV-01 on adult populations makes me therefore wonder whether this was driven at least in part due to concern that the tender infant respiratory system may be more prone to overreact to a potentially immunogenic siRNA molecule than a lung hardened by years of air pollution. This siRNA is probably unmodified as it was this June that the first Alnylam compounds using ISIS modification patents moved into IND-enabling studies. Being unmodified from a pharmacokinetic perspective may not be that bad or even desirable in RSV, as RSV is an acute infection and long drug exposure may therefore have the potential to do more harm than good.

I should emphasise, however, that the early rodent RSV studies that form the basis of Alnylam’s RSV-01 and which have supposedly been replicated by the company, demonstrated sequence-specific antiviral activities. Furthermore, from Alnylam’s presentations one can assume that RSV-01 was carefully screened for cytokine induction in a number of human cell lines and animal models. I should add as well that the slight delay of the RSV experimental infection model studies is not the result of any of these considerations, but more simply reflects the fact that finding volunteers to be infected with a virus that gives you flu-like symptoms and requires you to be locked away from the outside world for a couple of weeks, is not that easy. However, 74 of the 88 subjects, I suppose mostly students, have already been recruited and we should hear top-line data early next year.

Alnylam’s conservative approach to drug development is further demonstrated by their delay of filing INDs for their liver programs, for hypercholesterolemia and liver cancer. While there is no doubt that with current systemic delivery capabilities it is possible to achieve potent gene knockdown in the liver, the safety and dose-response data so far would explain Alnylam’s caution into committing to a particular formulation by year-end as originally guided. Instead, I agree with their assessment that with new chemistries coming online, such as MIT’s lipidoids which formed the basis of the recent microRNA saturation data in Nature, it is wise to keep testing all of to find the formulations that offer the best therapeutic index. It would not be the first time that a drug for treating heart disease would fail in a large-scale trial because of unacceptable side-effects seen in a handful of participants. For what it’s worth and mindful of the business considerations about demonstrating human proof-of-concept of an RNAi Therapeutics with the hypercholesterolemia program, I wonder whether Alnylam should not go first with liver cancer anyway.

Needless to say, this cautious, data-driven approach not only benefits Alnylam the Science, but also Alnylam the Business. The importance of their scientific credibility through publications and conference presentations cannot be underestimated when it comes to their ability to execute on their business development goals, mainly in the form of lucrative license deals and access to enabling technologies. With a cash position of $468M, Alnylam is in a stronger position than ever to focus on the long-term success of the company and its shareholders.



Rosetta Genomics on Track to Bring the First Clinical RNAi-related Product to Market

Almost unnoticed in the microRNA diagnostics space, Rosetta Genomics reported this week that it had completed the pre-validation phase for its first microRNA diagnostic product scheduled to come into the clinic in the first half of next year. It would be exciting to see the first RNAi-related product have a direct clinical impact and, if successful, will fund Rosetta’s microRNA diagnostics and therapeutics programs with minimal shareholder dilution. The microRNA diagnostic is designed to differentiate between squamous and non-squamous lung cancer which is not always possible to tell under the microscope and an area of particular importance now that Genentech’s VEGF-targeting MAb Avastin showed life-threatening side-effects particularly in subjects with squamous cell cancer.

While RNAi Therapeutics has attracted most of the RNAi attention, microRNA-based diagnostics are set to become the first commercial success of RNAi-related products in the clinic. Their differential expression, scalability, and, equally important, potential relative stability advantages compared to protein and larger mRNA biomarkers means that microRNAs have the potential to become the biomarker platform of choice. The (near) future should tell.

Opko Health Announces Initiation of First Phase III Trial of an RNAi Therapeutic

Less than a week after the signing of two significant alliances between RNAi Therapeutics companies with Big Pharma, it is today up to Opko Health to announce the initiation of the first phase III clinical trial for an RNAi Therapeutic. Opko Health is an ophthalmic focused company that was recently formed through a string of mergers and acquisitions with one of the companies involved being Acuity Pharmaceuticals. It is from Acuity that Opko inherited two advanced clinical RNAi Therapeutics programs, one of which is the subject of today’s announcement.

In the proposed COBALT study, Cand5 (bevasiranib), an unmodified siRNA against VEGF, will be given once every 8 or 12 weeks in patients with wet age-related degeneration (AMD). The goal is to assess its safety and, more importantly, whether it has equivalent efficacy compared to a the currently leading wet AMD drug Lucentis, which is another VEGF inhibitor that is given once every 4 weeks by needle injection.

Although the sweet spot for RNAi Therapeutics are targets that are otherwise undruggable by small molecules and monoclonal antibodies, Opko is one of a handful of companies targeting the VEGF pathway for AMD and diabetic retinopathy (see “RNAi and the Eye” post on May 1, 2007). This is in spite of the fact that other widely prescribed drugs, namely the monoclonal antibody Lucentis and the RNA aptamer by OSI Pharmaceuticals already serve this market. While this may reduce development risk and function as a proof-of-concept, RNAi Therapeutics for these applications will have to compete directly with such therapies in terms of safety and tolerability, potency, and duration of efficacy.

The reason why Opko wants to challenge Lucentis on duration is because each needle injection carries a risk of damaging the eye and causing discomfort to the mostly elderly patients. This becomes a particularly pressing issue for a repeat-administered therapy such as for wet AMD. Therefore, being able to reduce the frequency of injections by half or even more without a loss in efficacy would make an RNAi Therapeutics a very attractive treatment option. Indeed, pre-clinical studies published last year on the silencing of liver-expressed ApoB100 by systemic administration (Zimmermann et al. (2006) Nature 441: 111-4) support the notion that RNAi Therapeutics may have comparable or even better pharmacokinetics compared to what is usually observed for therapies such as monoclonal antibodies

While a positive outcome would certainly help the field of RNAi Therapeutics, there is cause to be skeptical. In particular, bevasiranib is an unmodified siRNA that is given without a particular performance enhancing formulation. This may result in suboptimal gene silencing due to RNA instability issues and inferior cell delivery and ultimately exhibit poor pharmacokinetics. Indeed, results from the C.A.R.E. phase II studies in 129 wet AMD patients were mixed and did not show statistically significant evidence for improvement of acuity. Opko clearly sees the need for optimizing RNAi delivery and have two years ago formed an alliance with the RNAi nano-delivery company Intradig to develop topical and other formulations for Cand5. Whether this will directly impact the current studies is unclear.

I am therefore more optimistic about the approach taken by Merck (formerly Sirna Therapeutics) and their partner Allergan to develop a slow-release formula of a modified siRNAs against the VEGF-receptor that when combined may significantly reduce the need for frequent needle injections. Phase II studies for that trial have started earlier this year.